BMET-35CERITINIB IN ALK+ NSCLC METASTATIC TO BRAIN AND/OR LEPTOMENINGES: THE ASCEND-7 STUDY

Abstract

BACKGROUND: The anaplastic lymphoma kinase inhibitor (ALKi) crizotinib achieves high responses in patients with ALK-rearranged (ALK+) non-small cell lung cancer (NSCLC). However, disease progression can occur within 1 year and the brain/central nervous system (CNS) is a common site of progression/relapse. Ceritinib is a novel oral ALKi with 20-fold greater potency than crizotinib in enzymatic assays and crosses the blood-brain barrier with good CNS penetration in preclinical studies. In phase 1 and 2 studies, ceritinib was highly active in ALK+ NSCLC patients (regardless of prior crizotinib exposure) and achieved intracranial responses in 31-59% of patients with measurable baseline brain lesions. METHODS: This international, prospective, phase 2, open-label study will evaluate the antitumor activity of ceritinib in patients with ALK+ NSCLC and active brain metastases (BM) or leptomeningeal carcinomatosis (LC), either with or without prior whole brain radiotherapy (WBRT) (ASCEND-7; NCT02336451). Eligible patients must have ALK+ (centrally assessed) NSCLC with active CNS metastases and ≥1 extracranial measurable lesion using Response Evaluation Criteria in Solid Tumors (RECIST) v1.1. Patients must be neurologically stable prior to study drug administration and will be allocated to 1 of 5 arms: active BM without LC, with prior ALKi exposure, with or without prior WBRT (Arms 1 and 2, respectively); active BM without LC, with no prior ALKi exposure, with or without prior WBRT (Arms 3 and 4, respectively); LC with or without evidence of active lesion at baseline (Arm 5). Oral ceritinib 750 mg/day will be dosed on a continuous schedule. The primary and key secondary objectives are to evaluate overall response rate and disease control rate, respectively. Other secondary objectives include assessment of intracranial and extracranial response for all patients and overall survival and safety for all patients in arms 1-4, including pharmacokinetics for each of arms 1-5. Enrollment is ongoing.